Dopamine is a biogenic amine present in the central nervous system (CNS), where it acts as a neurotransmitter. Dopamine exerts its effects by acting via five distinct G protein-coupled receptors (GPCRs) that are divided into two major groups, termed D1 (D1 and D5) and D2 (D2, D3, and D4). D1 receptors are expressed at high levels in the striatum, nucleus accumbens, substantia nigra, olfactory bulb, amygdala, and frontal cortex, and at lower levels in the hippocampus, cerebellum, thalamic areas, and hypothalamic areas. The highest levels of D2 receptors are found in the striatum, the nucleus accumbens, and the olfactory tubercle, with somewhat lower expression in the substantia nigra, ventral tegmental area, hypothalamus, cortical areas, septum, amygdala, and hippocampus. D1 receptors are generally Gs-coupled, and as such stimulate the production of the second messenger cAMP and the activity of PKA. In contrast, D2 receptors are generally Gi-coupled, and as such negatively regulate the production of cAMP and result in a decrease in PKA activity.
Dopamine has been implicated in a wide variety of biological processes ranging from voluntary movement and reward to hormonal regulation. Dopamine has also been implicated in pathological processes associated with disease states of the CNS. Pharmacological agents targeting dopaminergic neurotransmission have been used in the clinical management of several neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, bipolar disorder, Huntington's disease, attention deficit hyperactivity disorder (ADHD), and Tourette's syndrome. For example, haloperidol is a potent D2 receptor antagonist widely prescribed for the treatment of acute schizophrenic symptoms.
Described herein is another GPCR with high levels of expression in the CNS-G protein-coupled receptor 52 (GPR52) (NCBI Reference Sequence: NP_005675.3). GPR52 is highly conserved in vertebrates, with the human amino acid sequence sharing over 90% identity with the chimpanzee, bovine, mouse, rat, and chicken orthologs. As seen in the studies described herein, the highest expression levels within the human CNS are found in the striatum (see FIG. 17). Lower but significant expression levels are found in many other structures in the CNS, including the cortex (see FIG. 17). GPR52 co-localizes almost exclusively with the D2 receptor in the human and rodent striatum, and with the D1 receptor in the human and rodent cortex (see FIG. 18).
Several compounds are known to function as D1 agonists in the cortex, where they increase cortical function and resolve hypofrontality. As discussed herein, GPR52 co-localizes with the D1 receptor in the cortex. Because both GPR52 and D1 receptors are Gs-coupled, a GPR52 agonist should functionally resemble a D1 agonist—and therefore exhibit effects on cortical function and hypofrontality.
The efficacy of existing antipsychotic agents is reportedly mediated by D2 antagonist activity on medium spiny neurons (MSNs) in the striatum. However, D2 antagonists produce side effects, such as motor symptoms and hyperprolactinemia. As discussed herein, GPR52 co-localizes almost exclusively with the D2 receptor in the striatum. Because GPR52 is Gs-coupled and D2 is Gi-coupled, a GPR52 agonist should functionally resemble a D2 antagonist—and therefore exhibit antipsychotic efficacy. Further, because many of the side effects associated with D2 antagonists are mediated by the D2 receptor, GPR52 agonists could avoid the side effects associated with existing D2 antagonists.
Described herein are experiments in which GPR52 agonists were found to activate intracellular signaling and immediate early genes in neurons, affect electrical activity in neurons (similar to haloperidol and several existing antipsychotics), block amphetamine-stimulated locomotor activity (which mimics a hyperdopaminergic state), improve the ability to filter sensory information, and increase object recognition. Further, described herein are experiments in which unwanted activities associated with existing antipsychotics were avoided, including extrapyramidal side effects and prolactin release. The expression levels, co-localization, intracellular signaling, and functional properties described herein suggest that GPR52 is a significant modulator of brain function with relevance for the treatment of several neurological and psychiatric disorders, including those described below.
Hypofrontality
Decreased blood flow in the prefrontal cortex (hypofrontality) is symptomatic of several neurological conditions, including schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, and major depressive disorder. Dopaminergic transmission in the prefrontal cortex is mainly mediated by D1 receptors, and D1 dysfunction has been linked to cognitive impairment and negative symptoms in schizophrenia (Goldman-Rakic P S, Castner S A, Svensson T H, Siever L J, Williams G V (2004) Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology 174, 3-16). Increasing function in the prefrontal cortex with a GPR52 agonist is therefore useful for the treatment of symptoms associated with hypofrontality.
Movement Disorders
The striatum is involved in the control of movement. Pathology of the striatum is associated with many movement disorders, including hyperkinetic movement disorders characterized by excessive abnormal involuntary movements (known as hyperkinesias). Examples of hyperkinetic movement disorders include tremors, dystonia, chorea, ballism, athetosis, tics/Tourette's syndrome, Huntington's disease, myoclonus and startle syndromes, stereotypies, and akathisia.
In the striatum, GPR52 is almost exclusively expressed on neurons of the indirect striatal pathway. Hyperkinesias are associated with the dysfunction of inhibitory, D2-expressing neurons of this pathway. This dysfunction leads to the inability to inhibit movement, resulting in tics, chorea, vocalizations, tremors, and other hyperkinetic symptoms. For example, early hyperkinetic motor symptoms in Huntington's disease are the result of selective damage to the indirect, D2-containing pathway (Albin R L, Reiner A, Anderson K D, Penney J B, Young A B. (1990) Striatal and nigral neuron subpopulations in rigid Huntington's disease: implications for the functional anatomy of chorea and rigidity-akinesia. Ann Neurol. 27, 357-365). Further, D2 receptor binding in striatum is associated with the severity of Tourette syndrome symptoms (Wolf S S, Jones D W, Knable M B, Gorey J G, Lee K S, Hyde™, Coppola R, Weinberger D R (1996) Tourette syndrome: prediction of phenotypic variation in monozygotic twins by caudate nucleus D2 receptor binding. Science 273, 1225-1227).
The stimulation of GPR52 with agonists activates the indirect striatal pathway, leading to more inhibitory control over movement and the resolution of hyperkinetic symptoms. The GPR52 agonists disclosed herein are therefore useful for the treatment of such symptoms.
Psychotic Disorders
The psychotic symptoms of schizophrenia result from overactive presynaptic dopamine activity in the striatum (Howes O D, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull. 35, 549-562). The clinical efficacy of existing antipsychotic drugs for treating psychotic symptoms is dependent on blockade of the D2 receptor. All known antipsychotic drugs with efficacy for the treatment of psychosis are either antagonists or partial agonists at the dopamine D2 receptor (Remington G, Kapur S (2010) Antipsychotic dosing: how much but also how often?Schizophr Bull. 36, 900-903). While these antipsychotic drugs can treat the positive (or psychotic) symptoms of schizophrenia, they do not treat other aspects of schizophrenia, such as the negative symptoms or cognitive impairment. These antipsychotic drugs are also associated with significant side effect profiles, including weight gain, metabolic syndrome, diabetes, hyperlipidemia, hyperglycemia, insulin resistance, extrapyramidal symptoms, hyperprolactinemia, and tardive dyskinesia. Because GPR52 agonists should functionally resemble D2 antagonists, the GPR52 agonists disclosed herein are useful for the treatment of psychotic disorders.
Other D1-Related Disorders
Several neurological and psychiatric drugs are known to function as D1 agonists, including A-86929, dinapsoline, doxanthrine, SKF-81297, SKF-82958, SKF-38393, fenoldopam, 6-Br-APB, and stepholoidine. Because GPR52 agonists should functionally resemble D1 agonists (and are co-localized), the GPR52 agonists disclosed herein are useful for the treatment of disorders treatable by D1 agonists, including but not limited to addiction (e.g., cocaine addiction), cognitive and working memory deficits in schizophrenia and schizotypal disorder, psychotic disorders, hypertension, restless leg syndrome, Parkinson's disease, and depression.
Other D2-Related Disorders
Several neurological and psychiatric drugs are known to function as D2 antagonists, including atypical antipsychotics (e.g., aripiprazole, clozapine, olanzapine, and ziprasidone), domperidone, eticlopride, fallypride, desmethoxyfallypride, L-741,626, raclopride, hydroxyzine, itopride, SV 293, typical antipsychotics, yohimibine, amisulpride, and UH-232. Because GPR52 agonists should functionally resemble D2 antagonists, the GPR52 agonists disclosed herein are useful for the treatment of disorders treatable by D2 antagonists, including but not limited to psychotic disorders, detachment, anxiety, anxiety/tension associated with psychoneurosis, acute mania, agitation, mania in bipolar disorder, dysthymia, nausea, vomiting, gastrointestinal conditions, dyspepsia, and addiction (e.g., cocaine addiction, amphetamine addiction, etc.).
There is a need for alternative compounds for the treatment of neurological and psychiatric disorders. The compounds described herein satisfy this need and provide related advantages as well.